Patent EA-004501-B1 (EA)
Title: 2.4-disubstituted triazine derivatives
Inventor: DE CORTE BART
IPC: A61K31/53
Filed: 1999-11-04
Abstract: 1. A compound of formula a N-oxide, an addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein R<1> is hydrogen, aryl, formyl, C1-6alkylcarbonyl, C1-6alkyl, C1 6alkyloxycarbonyl, C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl; R<2A> cyano or aminocarbonyl; L is -X-R<3>, wherein R<3> is phenyl, optionally substituted with two, three, four or five substituents each independently selected from the substituents defined in R<2>; each R<2> is independently hydroxy, halo, C1-6alkyl, optionally substituted with cyano or -C(=) R<4>, C3-7cycloalkyl, C2-6alkenyl, optionally substituted with one or more halo or cyano atoms; C2-6alkynyl, optionally substituted with one or more halo or cyano atoms; C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl) amino, polyhalomethyl, polyhalomethyloxy, polyhalogenmethylthio, -S(=O)pR<4>, -NH-S(=O)PR<4>, -C(=O) R<4>, -NHC (=O) H, -C(=O) NHNH2, -NHC (=O) R<4>, -C (=NH) R<4> or a radical of formula in which each A is independently N, CH or CR<4>; B is NH, O, S or NR<4>; p is 1 or 2; and R<4> is methyl, amino, mono- or dimethylamino or polyhalogenmethyl; X is -NR<1>-, -O- or -S-. aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl and polyhaloC1-6alkyloxy. 2. A compound of formula a N-oxide, an addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein R<1> is hydrogen, aryl, formyl, C1-6alkylcarbonyl, C1-6alkyl, C1 6alkyloxycarbonyl, C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl; R<2A> cyano or aminocarbonyl; L is -X-R<3>, wherein R<3> is phenyl, optionally substituted with two, three, four or five substituents each independently selected from the substituents defined in R<2>; each R<2> is independently hydroxy, halo, C1-6alkyl, optionally substituted with cyano or -C(=) R<4>, C3-7cycloalkyl, C2-6alkenyl, optionally substituted with one or more halo or cyano atoms; C2-6alkynyl, optionally substituted with one or more halo or cyano atoms; C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl) amino, polyhalomethyl, polyhalomethyloxy, polyhalogenmethylthio, -S(=O)pR<4>, -NH-S(=O)PR<4>, -C(=O) R<4>, -NHC (=O) H, -C(=O) NHNH2, -NHC (=O) R<4>, -C (=NH) R<4> or a radical of formula in which each A is independently N, CH or CR<4>; B is NH, O, S or NR<4>; p is 1 or 2; and R<4> is methyl, amino, mono- or dimethylamino or polyhalogenmethyl; X is -NR<1>-, -O- or -S-. aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl and polyhaloC1-6alkyloxy. 3. A compound as claimed in any one of claims 1 and 2 wherein L is -X-R<3>, -X- is -O- or -NH- and R<3> is phenyl substituted with two or three substituents each independently selected from chloro, bromo, cyano and methyl. 4. The use of a compound for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection. 5. A compound as claimed in any one of claims 1 to 3 for use as a medicine. 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of compound as claimed in any one of claims 1 to 3. 7. A process for preparing a pharmaceutical composition as claimed in claim 7 characterized in that a therapeutically effective amount of a compound as claimed in any one of claims 1 to 3 is intimately mixed with a pharmaceutically acceptable carrier. 8. A process for preparing a compound as claimed in any one of claims 1 to 3, or a N-oxide, an addition salt, a quaternary amine or a stereochemically isomeric form thereof, characterized by a) reacting an intermediate of formula (II) with an amine derivative of formula (III) and subsequently reacting the thus obtained intermediate of formula (IV) with an inter-mediate of formula (V) in a reaction-inert solvent in the presence of a suitable base; wherein W<1> is a suitable leaving group, R<2> is R<2A>; R<1>-R<3>; X and R<2A> are as defined in claim 1, n is 1 and -a<1>=a<2>-a<3>=a<4>- is -CH=CH-CH=CH-; and, if desired, converting compounds of formula (I') into each other following art-known transformations, and further, if desired, converting compounds of formula (I') into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing stereochemically isomeric forms or N-oxides thereof. 9. The combination of a compound as defined in any one of claims 1 to 3 and another antiretroviral compound. 10. A combination as chinned in claim 9 for use as a medicine. 11. A product containing (a) a compound as defined in any one of claims 1 to 3, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound as defined in any one of claims 1 to 3, and (b) another antiretroviral compound.